This proposal is for a three year training program at Case Western Reserve University (CWRU) for the development of a career in academic experimental immunology. The principal investigator, a Ph.D. in molecular biology who is now completing postdoctoral training in molecular immunology, will expand upon his skills and transition to independent research through an integrated program involving further work with his mentor and other investigators.The program will expand knowledge in the interplay of complement activation and cytokine generation in the settings of digestive and particularly renal diseases and in therapeutics in animal models. Dr. Edward Medof will mentor the PI's scientific development. He is a recognized leader in complement regulatory proteins that protect self tissues from complement attack, and pioneered research in the decay accelerating factor (DAF), the first of these to be described. He is a Professor in Pathology, is Associate Director of the CWRU Immunology Postdoctoral and Predoctoral Training Programs, and has trained numerous postdoctoral fellows and graduate students. To enhance the training, the program will include Dr. Steven Emancipator, Professor of Pathology, an authority in immunological diseases of the kidney, Dr. Alan Levine, Associate Professor of Medicine, a recognized expert in cytokines and inflammatory bowel disease, Dr. David Salant, Chief of Nephrology at Boston University, a world renowned expert in antibody-induced renal diseases, and Dr. Peter Heeger, an expert of cellular immune mechanisms. Additional faculty will provide scientific and career advice.Research will focus on inflammatory mediators that are generated in experimental models of inflammatory bowel disease and particularly nephritis. The applicant has generated a DAF knockout mouse and shown that in the absence of DAF, tissue injury is greatly enhanced in nephrotoxic serum-induced nephritis and dextran sulfate sodium-induced colitis and in delayed, possibly NK cell-mediated allograft rejection. Specific aims are to 1) define the patterns and site(s) of cytokine production in the two disorders and characterize the mechanism of allograft rejection, 2) investigate these issues in related diseases, and 3) explore the effects of targeted recombinant DAF modules on disease pathogenesis. The results will constitute the first in vivo analysis of the interplay between complement activation and cytokine production, and could have therapeutic benefits.The integrated research activities at CWRU encompassing Pathology, Medicine, and the Biomedical Sciences Training Program incorporate diverse expertise and a full range of state-of-the-art facilities that provide an ideal setting for training in specific programs. It should maximize the opportunity for a promising young scientist to develop a niche for an independent career.